Frontiers in Microbiology · Nov 5, 2026
The Gut Microbiome in Skeletal Homeostasis and Osteoporosis: A Triangulation of Mechanistic, Clinical, and Mendelian Randomization Evidence
By Xian Wang, Min Chen, Jinghua Du et al.
Osteoporosis is a multifactorial skeletal disorder characterized by progressive bone loss, disruption of trabecular and cortical microarchitecture, and compromised biomechanical competence, resulting in susceptibility to fragility fractures and substantial morbidity. Despite advances in anti-osteoporotic pharmacotherapy, current interventions target downstream consequences of skeletal imbalance rather than the molecular, immunological, metabolic and environmental determinants of disease initiation and progression. Emerging evidence identifies the gut microbiota as an important regulator of skeletal physiology, revealing the gut–bone axis as an underappreciated network integrating microbial metabolism, barrier function, immune homeostasis, inflammatory regulation, and endocrine signalling to influence bone remodeling. Firstly, we examined how microbiota-derived metabolites, namely short-chain fatty acids (SCFAs), trimethylamine-N-oxide (TMAO), tryptophan-derived indoles and bile acids, link intestinal microbial activity to osteoblast and osteoclast biology. These metabolites act through immunometabolic and endocrine pathways involving regulatory T-cell differentiation, Wnt/β-catenin signalling, RANKL-dependent osteoclastogenesis, oxidative stress and inflammatory cytokines. Secondly, clinical evidence links alterations in gut microbial composition and functional capacity, intestinal barrier integrity, and circulating metabolomic profiles to impaired bone mineral density (BMD), accelerated skeletal turnover, and increased fracture susceptibility in postmenopausal women and patients with metabolic disorders. Thirdly, we examined the emerging contribution of Mendelian randomization (MR) and other genetically informed methodologies, identifying potential associations, but not causal links, among specific microbial taxa, microbiota-derived metabolites, and clinically relevant skeletal outcomes. We further assessed dietary, probiotic, prebiotic and pharmacological strategies targeting the gut–bone axis, together with the context-dependent nature of microbiota-mediated regulation. By integrating mechanistic outcomes from experimental models, translational observations from clinical cohorts, and genetically informed evidence, this review synthesizes microbiota-driven regulation of bone metabolism. Across these streams, however, no target reaches concordance: most pathways rest on a single study design, apparent replication across MR studies often reflects shared GWAS resources rather than independence, and no gut-derived biomarker has been validated prospectively. We apply an explicit evidence grade to every claim: findings supported only by rodent or in vitro work are identified as such, and no microbiota-targeted intervention has been shown to reduce fractures in humans.